Clinical Implications Among Immune Response, Immune Checkpoints, Monoamine Oxidases, HABP4 and SERBP1 Proteins in Bladder Cancer: Possible Clinical Biomarkers

• Grant number: 22/09698-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): November 01, 2022
• Effective date (End): October 31, 2023
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Wagner José Fávaro
• Grantee: Isadora Manzato Roberto
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Bladder cancer (BC) is the most common malignancy of the urinary tract and one of the most prevalent cancers worldwide. As the overall prognosis of BC has not changed over the past 30 years, there is a pressing medical need to develop new diagnostic and therapeutic approaches. Bacillus Calmette-Guerin (BCG) immunotherapy is the most effective form of intravesical therapy for the prophylaxis of recurrence and progression of non-muscle invasive bladder cancer (NMIBC). However, BCG immunotherapy is often associated with local and/or systemic adverse effects, including sepsis, in addition to tumor recurrence in up to 40% of cases. Although cystectomy is the gold standard for the treatment of cases unresponsive to BCG and muscle invasive tumors (MIBC), this procedure entails significant changes in morbidity, mortality, and quality of life. The advent of immune checkpoint immunotherapies has revolutionized the standard of care for patients with metastatic bladder cancer, repositioning their use for patients with BCG-unresponsive NIMBC. Currently, new immunotherapeutic agents have yet to surpass the efficacy of the gold standard BCG. Due to the inherent complexity of the immune response, patient selection and the development of biomarkers to guide the identification of patients who will derive the greatest benefit from a given immunotherapy remain critical. Most immunotherapies act by enhancing the antitumor responses of CD8+ T cells, which can be severely limited by the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a key component of the immunosuppressive TME, decrease anti-tumor T cell reactivity in most solid tumors. In recent years, several studies have demonstrated the upregulation of monoamine oxidase A (MAO-A) in neoplastic tissues compared to normal tissues, and MAO-A expression has been associated with metastasis and decreased overall survival in various types of cancers. Hyaluronic acid binding protein 4 (=HABP4) is functionally involved in transcriptional regulation and RNA metabolism and has several features common to oncoproteins or tumor suppressors. This protein is expressed in different types of tissues and, as a paralog of the Serpin mRNA Binding Protein 1 (=SERBP1), it is involved in important cellular events, which are usually disrupted during tumorigenesis processes. Although many functional characteristics tend to overlap between HABP4 and SERBP1, in relation to cancer, the data so far point in opposite directions, as SERBP1 has been reported to be overexpressed in several cancer settings, including ovarian, breast, colon, prostate, glioblastoma and lung cancer. Thus, the roles of MAO, HABP4 and SERBP1 in bladder cancer are still poorly explored. Therefore, this project will aim to characterize and compare the inflammatory/immune response profiles, monoamine oxidases and HABP4 and SERBP1 proteins in both healthy and neoplastic (NMIBC, BCG-unresponsive NIMBC and MIBC) human urinary bladder samples; as well as establish an informative overview of these interrelated factors and signaling pathways and implicated in the complex microenvironment of bladder cancer. Furthermore, this project will verify whether the MAO (MAO-A, MAO-B), HABP4 and SERP1 biomarkers will have any relevance in bladder cancer diagnosis, risk stratification, outcome prognosis and response prediction to therapies, including immunotherapies.